Investigation and Development of a Whole-Cell Model for a Minimal Synthetic Organism

最近合成生物学领域的一个重要焦点是研究最小基因组。截至2016年，最小的基因组是Mycoplasma mycoides JCVI-syn3.0，这是一种衍生自Mycoplasma mycoides |的合成细菌，因为它生长快，所以复制的周转迅速，因此被选择用于基因组最小化项目。遗传物质根据科学家们设计的一套规则从基因组中移除，试图找到并移除所有非必要的遗传物质。在901个支原体基因中，有428个被移除，但31%的“必要”基因功能未知，因此在解开它们在基因组中的作用方面仍有工作要做。目前，由于对某些基因的功能和某些遗传信息的必要性缺乏了解，许多最小化基因组的工作都是试错的，因此可以分析基因组并分离多余遗传物质的算法将在这一领域非常有用。这也有助于简化全细胞模型。生物信息学是一种有用的工具，它可以通过数据分析来发现基因，从而揭示遗传物质的功能，从而在某种程度上破译遗传密码。我提议的研究是最小化基因组工作的延续。目前，有一个工作的MATLAB模型来模拟生殖支原体，该模型由28个子模型组成，这些子模型用于集成在一起的不同细胞过程。每个过程都使用适当的数学方法，例如代谢的x平衡分析和蛋白质降解的泊松过程。考虑到模型的规模，运行和处理需要大量的时间和大量的输出数据。此外，这些模型仅对简单生物的分析有用，但有机会开发其他单细胞生物的模型；例如JCVI-syn3.0。这些可以用来预测某些基因的缺失对细胞功能的影响，最终可能表明哪些基因对细胞的生存是多余的，并证明哪些基因是生命的基本要求。此外，这可以在实验室工作中验证，从活细胞中取出遗传物质，看看它们是否繁殖。这些信息可以用于设计具有所需功能的新合成生物体。

A signicant focus in the Synthetic Biology eld has recently been investigating minimal genomes. Asof 2016, the smallest genome is that of Mycoplasma mycoides JCVI-syn3.0, which is a synthetic bacteriumderived from Mycoplasma mycoides | selected for the genome-minimisation project because it grows fast,so the turnaround of replication is ecient. Genetic material was removed from the genome accordingto a set of rules devised by the scientists, in an attempt to locate and remove all of the non-essentialgenetic material. Of the 901 mycoplasma genes, 428 were removed, but 31% of the `essential' genes haveunknown functions, so there is still work to be done in unravelling their role in the genome. Currently, alot of the minimising genome work has been trial-and-error, due to lack of knowledge about the functionof certain genes and the necessity of some genetic information, so algorithms that could analyse genomesand isolate surplus genetic material would be hugely useful in this area. This would also contributetowards simplifying whole-cell models. Bioinformatics is a useful tool that can indicate the function ofgenetic material by nding genes though data analysis | going some way to deciphering genetic code.The research that I am proposing is a continuation of the minimising genome work. Currently, thereis a working MATLAB model that simulates Mycoplasma genitalium, which consist of 28 submodelsfor di erent cell processes that are integrated together. Appropriate mathematical methods are used foreach process, such as ux-balance analysis for metabolism, and Poisson processes for protein degradation.Given the scale of the model, running and processing requires a lot of time and there are large amountsof output data. Additionally, the models are only useful for the analysis of simple organisms, but there isopportunity to develop models for other unicellular organisms; for example JCVI-syn3.0. These can beused to predict the impact that deletion of certain genes will have on the cell function, which eventuallymay indicate which genes are superfluous to the survival of the cell, and demonstrate which genes are thebasic requirements for life. Also, this can be veried in lab work, where genetic material is removed fromliving cells to see if they flourish or not. The information could then be applied to design new syntheticorganisms possessing desired functions.